The goal of these experiments is to examine the memory component of behavioral tolerance to chronic administration of ethanol. We propose that learned tolerance involves activation of systems that may modulate complex learning and memory processes in mice. Current evidence suggests that brain protein kinase C may modulate some forms of learning and memory. To examine whether activation of protein kinase C is involved in the development of tolerance to ethanol, a genetic approach will be used. C57BL/6 mice which develop tolerance to the hypothermic effects of ethanol after intraperitoneal administration will be compared to DBA/2 mice which do not show pronounced tolerance to the hypothermic effects of ethanol after repeated administration. Previous experiments from this laboratory have shown that C57BL/6 and DBA/2 mice also differ in complex learning performance and hippocampal protein kinase C activity. Thus a relationship may exist between these parameters and the development of learned tolerance to ethanol. Learned tolerance to ethanol will be examined using two different routes of administration which differ in the complexity of environmental cueing and handling of the animals: 1) to maximize cueing, ethanol will be administered via intraperitoneal injections and body temperature will be monitored in mice handled daily and tested in different environments and 2) to minimize cueing, mice will receive intravenous administration of ethanol with constant monitoring of body temperature using minimitter systems. Dose-response and time-course experiments will be performed. Biochemical measurements of protein kinase C and phorbol ester binding in seven brain regions including hippocampus will be performed during and after ethanol treatment. After optimal conditions are selected, changes in potential protein kinase C phosphoprotein substrates will be measured as a function of ethanol tolerance in C57BL/6 and DBA/2 brain slices. Lastly, a BXD recombinant inbred strain study will be performed to assess whether common genes mediate the development of learned tolerance to ethanol, protein kinase C activity, or measurements of complex learning performance. These studies should provide new information concerning the role of learning and memory systems in the development of ethanol tolerance.